Project Summary The threat of a radiation attack or accident is, unfortunately, all too real and could potentially affect a large enough population so as to overwhelm the medical system. To be prepared for such an event, it is necessary to stockpile effective radiation medical countermeasures (MCM) that are safe, easily administered to large numbers of people, and effective even when treatment is delayed 24-48 hrs after radiation exposure. Radiation exposure has the most damaging affects on rapidly dividing, undifferentiated cells. As such, the bone marrow and epithelium of the gastrointestinal tract are particularly harmed by radiation exposure. Acute Radiation Syndrome (ARS) is often divided into sub- syndromes based upon the observed symptoms. The hematopoietic sub-syndrome (H-ARS) results in neutropenia, anemia, and thrombocytopenia. Depending upon the species, death can occur within 2-4 weeks. The gastrointestinal sub-syndrome (GI-ARS) is characterized by cell death in the intestinal epithelium followed by disintegration of the intestinal wall and death from fluid and electrolyte imbalance, intestinal bleeding and sepsis. Death by GI-ARS is more rapid than that for H-ARS, generally occurring within 10 days. One promising approach that has been shown to treat multiple aspects of ARS, but especially GI-ARS, is the use of ghrelin, a peptide hormone produced in the gut which stimulates appetite, reverses muscle atrophy in cancer- and chemotherapy-induced cachexia and other wasting conditions, promotes gut motility, reduces inflammation, and restores the health of the intestinal lining. But the use of ghrelin currently requires multiple daily doses due to its poor pharmacokinetic properties. Extend Biosciences has a platform technology that harnesses the biology of vitamin D to improve the half-life and bioavailability of peptides. In our preliminary work, we have developed a constitutively active, long-acting version of ghrelin (EXT405) that could be administered far less frequently than native ghrelin and may provide improved benefits over native ghrelin for GI- ARS. In this SBIR Phase I proposal, we will demonstrate the feasibility of our improved ghrelin in ARS efficacy models in mice when given subcutaneously 24 hr following exposure. Our milestones are to be able to dose less frequently vs. native ghrelin. EXT405 also has the potential to more effectively mitigate the effects of ARS vs. native ghrelin. Self-administration of 1-2 doses of EXT405 would better suit the needs of victims of ARS during an emergency than ghrelin alone.